Possible preferential metabolism of xylene isomers following occupational exposure to mixed xylenes

Abstract

Objectives: Solvent exposures commonly involve mixtures of substances or mixtures of isomers of a single solvent. These may be metabolised through common pathways, resulting in the potential for metabolic interactions. These may then lead to accumulation of solvent or metabolic intermediates, some of which may be toxic. This paper describes a pilot study conducted to determine the correlation between airborne xylene isomers and the appearance of methylhippuric acid (MHA) isomers in urine of workers exposed mainly to xylene. The project also aimed to determine whether there is preferential metabolism of any isomer by comparison of the ratios of airborne isomers with the ratios of metabolite isomers appearing in urine. Subjects and methods: A total of 12 workers (11 male, 1 female) were recruited into this study, with 2 of the participants providing samples on more than one occasion. Workers included flooring contractors (5), printers (2), chemical manufacturers (2), histology technicians (2) and one householder using a xylene-based varnish. Subjects were aged between 24 and 48 years (37.6 ± 2.0 years; mean ± SEM). After giving informed consent, workers provided a prework and postwork urine sample on a midweek work day. Samples were stored frozen prior to analysis. Breathing-zone air samples were collected using personal air samplers at 50 ml/min. Solvents were trapped on activated-charcoal sampling tubes. Subjects wore pumps for 18–304 (178 ± 24) min on the same day on which urine samples were collected. Results: Xylene exposures ranged from 1.6 to over 7000 ppm. In all, 7 of 16 measurements exceeded the Australian TWA standard of 80 ppm. Two of the flooring contractors wore respiratory protective equipment (RPE) and the two histopathology technicians used workplace ventilation systems. Total urinary MHA output ranged from 10 to 8000 mmol/mol creatinine, with 6 of 16 samples exceeding the modified biological exposure index of 702 mmol/mol. Correlations between airborne concentrations of individual xylene isomers and their corresponding MHA isomers were poor but improved when workers using RPE were excluded from the analysis. Gradients of the regression lines (millimoles of MHA per mole of creatinine per parts per million of xylene) were 3.2 for o-isomers, 7.0 for p-isomers, and 14.4 for m-isomers. Comparisons of isomer ratios of xylene in air were made with the corresponding ratio of MHA isomers in urine. These revealed higher ratios of m-MHA to other MHA isomers than those of m-xylene to the other xylene isomers. The MHA isomer ratios were expected to be the same as the airborne xylene isomer ratios if there were no preferential elimination of any isomer. m-MHA appeared in urine in a greater proportion than would be predicted from the proportion of m-xylene detected in air. The time course of the appearance of MHA isomers in urine also suggests that interactions were taking place, with m-MHA appearing in high proportion in urine following several days of repeated heavy xylene exposure. On a single moderate exposure, m-MHA appeared initially in high proportion in the first few hours but was undetectable in urine after 18 h. p-MHA was detectable for up to 6 h after exposure, and o-MHA remained detectable after 18 h. Conclusions: This study suggests that excretion of m-MHA in urine is favoured over that of the other isomers following exposure to mixed xylenes. This is independent of airborne xylene isomer composition and suggests that the metabolism of m-xylene occurs preferentially to that of the other isomers. It is not clear at which step in the metabolism of xylene this preference occurs, although other work indicates that the initial oxidation of xylene to methylbenzyl alcohol by cytochrome P450 2E1 occurs at the same rate for each isomer. These findings suggest that there is potential for metabolic interactions between xylene isomers and that these may be the basis for xylene toxicity.